A phase I trial of sorafenib (BAY 43–9006) for patients with recurrent or progressive malignant glioma (NABTT 0401)

Abstract

2058 Background: Sorafenib (BAY 43–9006) is a small molecule inhibitor of multiple kinases to include raf, VEGF receptors, and PDGF receptors. The molecule has demonstrated anti-proliferative and anti-angiogenic activity in a number of in vitro and in vivo model systems. Methods: In this multi-institutional trial, we have conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Cohorts of 3 patients, stratified based on the use of enzyme inducing anticonvulsants (EIAC) or not (non-EIAC), have completed enrollment through the following dose levels: 200 mg, 400 mg, 600 mg, and 800 mg. Therapy has been given as a twice daily oral administration with cycles of 28 day duration. Results: A total of 35 patients have been enrolled and are evaluable for toxicity. Treatment related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematological toxicity, and grade 4 hematological toxicity (platlets and ANC) or febrile neutropenia of any duration. The following DLTs were observed: one grade 3 hand-foot-syndrome at the 400 mg BID (EIAC), one grade 3 puritis 400 mg BID (non-EIAC) dose level, grade 3 hand/foot syndrome 800 mg BID (EIAC and non-EIAC arms), grade 3 hypophosphatemia 800 mg BID (EIAC), and grade 3 joint pain 800 mg BID (EIAC). A MTD of 600 mg BID has been defined for the EIAC arm with 3/6 DLTs at 800 mg BID. A MTD has not been defined and enrollment has been completed through the 800 mg BID dose level for the non-EIAC. Of the enrolled patients, 20 are with glioblastoma multiforme (GBM), 8 with anaplastic astrocytoma (AA), and 7 with anaplastic oligodendroglioma (AO). Conclusions: The MTD for sorafenib is 600 mg BID for patients on EIAC. Sorafenib is well tolerated with limited toxicities to doses of 800 mg twice daily in patients with recurrent malignant glioma not on EIAC (non-EIAC arm). No significant financial relationships to disclose.